PURPOSE: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management. METHODS: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment. RESULTS: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. CONCLUSION: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

The etiology of familial breast cancer is complex and involves genetic and environmental factors such as hormonal and lifestyle factors. Understanding familial aggregation is a key to understanding the causes of breast cancer and to facilitating the development of effective prevention and therapy. To address urgent research questions and to expedite the translation of research results to the clinical setting, the National Cancer Institute (USA) supported in 1995 the establishment of a novel research infrastructure, the Breast Cancer Family Registry, a collaboration of six academic and research institutions and their medical affiliates in the USA, Canada, and Australia. The sites have developed core family history and epidemiology questionnaires, data dictionaries, and common protocols for biospecimen collection and processing and pathology review. An Informatics Center has been established to collate, manage, and distribute core data. As of September 2003, 9116 population-based and 2834 clinic-based families have been enrolled, including 2346 families from minority populations. Epidemiology questionnaire data are available for 6779 affected probands (with a personal history of breast cancer), 4116 unaffected probands, and 16,526 relatives with or without a personal history of breast or ovarian cancer. The biospecimen repository contains blood or mouthwash samples for 6316 affected probands, 2966 unaffected probands, and 10,763 relatives, and tumor tissue samples for 4293 individuals. This resource is available to internal and external researchers for collaborative, interdisciplinary, and translational studies of the genetic epidemiology of breast cancer. Detailed information can be found at the URL http://www.cfr.epi.uci.edu/ .

Background: Having a family history of breast cancer, particularly if it involves early-onset disease, is a risk factor for breast cancer, but little is known about specific causes of this association. Consequently, we studied mothers, sisters, and aunts of an age-stratified sample of 1567 unselected case patients diagnosed with breast cancer before age 60 years, recruited to a population-based, case–control-family study, in which case patients, control subjects, and their relatives were administered the same questionnaire. Methods: Extensive BRCA1 and BRCA2 mutation testing was carried out for 788 case patients diagnosed before age 40 years, including manual sequencing of DNA from 72 patients with two or more affected relatives. Standardized morbidity ratios, age-specific cumulative risks, and hazard ratios were calculated for groupings of relatives. Results: Cumulative risks of breast cancer to age 50 years in the sisters, mothers, and aunts of the case patients, respectively, were 6, 3, and 2 times the population risk if the case patient was younger than age 40 years at diagnosis but were considerably lower if the case patient was older at diagnosis. When relatives of the case patients with a BRCA1 or BRCA2 mutation were excluded, these risks fell by, at most, 20%. Sisters and aunts, but not mothers, who had an additional first-degree relative with breast cancer were at increased risk, and the risk was greater when that relative was younger at diagnosis. Hazard ratios were 10.7 (95% confidence interval [CI] = 4.2 to 26.8) for sisters and 4.2 (95% CI = 2.2 to 8.1) for aunts, if the relative was aged 40 years at diagnosis. Fewer than one-third of the excess of breast cancers in relatives of case patients diagnosed before age 40 years that are attributed to familial factors are BRCA1- or BRCA2-related. Conclusion: Mutations in genes other than BRCA1 and BRCA2 may be associated with a high risk of breast cancer, especially in young women.

Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35–85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (–0.46 cm [95% CI: −0.53, −0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I²) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was −0.24 cm (95% CI: −0.34, −0.14; I² = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (−0.38 cm [95% CI: −0.44, −0.33]; I² = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.

The evidence that mutations in the HFE gene for hemochromatosis are associated with increased cancer risk is inconsistent. The Melbourne Collaborative Cohort Study is a prospective cohort study that commenced recruitment in 1990. Participants born in Australia, New Zealand, the United Kingdom, or Ireland (n = 28,509) were genotyped for the HFE C282Y (substitution of tyrosine for cysteine at amino acid 282) variant. Incident cancers were ascertained from Australian cancer registries during an average of 14 years follow-up. Hazard ratios (HRs), confidence intervals (CIs), and P values were obtained from separate Cox regression analyses for colorectal, breast, and prostate cancers, all other solid cancers, and all cancers. Compared to those with no C282Y variant, C282Y homozygotes were at increased risk of colorectal cancer (HR = 2.28; 95% CI = 1.22, 4.25; P = 0.01) and female C282Y homozygotes were at increased risk of developing breast cancer (HR = 2.39; 95% CI = 1.24, 4.61; P = 0.01), but male C282Y homozygotes were not at increased risk for prostate cancer (HR = 0·96; 95% CI = 0·43, 2·15; P = 0.92). C282Y/H63D compound heterozygotes were not at increased risk for colorectal cancer (HR = 1.27; 95% CI = 0.80, 2.01), breast cancer (HR = 1.16; 95% CI = 0.74, 1.84), or prostate cancer (HR = 1.08; 95% CI = 0.68, 1.70). Conclusion: HFE C282Y homozygotes have twice the risk of colorectal and breast cancer compared with those individuals without the C282Y variant. (HEPATOLOGY 2010.)